Packaging meterials for transdermal drug delivery systems

ABSTRACT

Compositions and methods for producing laminate materials in packaging a transdermal drug delivery system comprising a rubber modified acrylonitrile methyl acrylate copolymer film, alone or in combination with a polyester film, wherein the active drug incorporated in the transdermal system remains substantially solubilized and stable in the system during storage prior to use. The packaging laminate is preferably translucent to allow visual inspection of its contents, and has sufficient tear resistance to substantially provide child resistant and/or proof properties.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.10/751,587, filed Jan. 5, 2004, which is a continuation-in-partapplication of U.S. patent application Ser. No. 09/804,926, filed Mar.13, 2001, which is expressly incorporated by reference in its entirety,and which claims the benefit of U.S. Provisional Application Ser. No.60/189,333 filed Mar. 14, 2000, which is expressly incorporated byreference in its entirety.

BACKGROUND OF THE INVENTION

This invention relates generally to packaging materials for transdermaldrug delivery systems and, more particularly, to materials and methodsof providing transdermal system packaging that improves stability andshelf-life of the drug during storage.

The use of transdermal drug delivery systems or “patches” as a means totopically administer a drug is well known. Such systems incorporate thedrug into a carrier composition, such as a polymeric and/orpressure-sensitive adhesive composition, from which the drug isdelivered at therapeutically effective amounts by absorption throughskin or mucosa of the user.

Such transdermal systems are commercially available for drugs such asnitroglycerin, nicotine, estradiol, lidocaine and other pharmaceuticals.These transdermal drug delivery devices typically are affixed adhesivelyto the skin or mucosa of a user, and the drug diffuses at a controlledrate from a polymer reservoir or layer into the skin or mucosa andabsorbed into the blood.

Conventional transdermal systems rely upon administration of solubilizeddrug. The ability of a transdermal system to deliver a therapeuticallyeffective amount of a drug for the intended duration of use generallyrequires that the drug remain solubilized and stable in the carriercomposition while in storage prior to use.

It is known that certain formulational factors can affect the stabilityof a drug in a transdermal system. Such formulational factors generallyrelate to the chemical reactivity between the various components makingup the drug carrier composition, such as adhesives, solvents andenhancers. For example, many transdermal systems use a pharmaceuticallyacceptable pressure-sensitive adhesive as the means to contain the drugand/or attach the system to a user. However, it has been found that thefunctionality of these adhesives can significantly affect the drug'ssolubility in the carrier compositions, thereby altering drug flux uponapplication to the user.

Many transdermal systems rely upon enhancers to improve or increasepenetration of the drug at the site of application of the system.However, certain enhancers may react with drugs to cause theirdegradation into by-products that can interfere with drug penetrationand delivery. See, for example, U.S. Pat. No. 6,024,974.

It is also well known that common environmental factors such as thepresence of water (in liquid or vapor form), air and/or light can alsoadversely affect the stability of some drugs. See, for example, U.S.Pat. No. 5,077,104. Such environmental factors can also affect thesolubility of the drug in the carrier composition which in turn can alsosignificantly impact the storage stability or shelf-life of thetransdermal system. For example, moisture tends to promote crystalgrowth or formation for many drugs during storage of a transdermalsystem. Since only solubilized drug is available for delivery out of atransdermal system, the package or container for the transdermal systemmust provide a barrier to such environmental factors.

Product packaging is usually configured in a manner that defines a spaceto surround the transdermal system, such as a pouch, in order to provideprotection from the environment. The product packaging can be flexibleor rigid. Suitable materials used, whether singularly, in combination,as laminates (cold sealed, heat sealed or flood or pattern coated withnatural or synthetic adhesives) or as coextrusions, to form thepackaging are well known in the art and include films or sheets ofpolyethylene, polyester, polypropylene, polyurethane, polyolefin,polyvinyl alcohol, polyvinyl chloride, polyvinylidene, polyamide, vinylacetate resins, BAREX®, ethylene/vinyl acetate copolymers,ethylene/ethylacrylate copolymers, metal-vapor deposited films or sheetsthereof, rubber sheets or films, expanded synthetic resin sheets orfilms, non-woven fabrics, fabrics, knitted fabrics, clothes, foils andpapers.

U.S. Pat. No. 5,008,110 discloses that certain polyolefin materials usedfor transdermal devices tend to absorb lipophilic solvents and/orenhancers, which can significantly decrease the drug's solubility in thecarrier composition, as well as cause physical failure of the packagingmaterial.

U.S. Pat. No. 4,943,435 discloses that nicotine will adversely affectmany common transdermal system component materials such as adhesives,membranes, backings and release liners.

It has been unexpectedly discovered that methylphenidate can be unstableand lost by absorption in the presence of certain types of packagingmaterials used for transdermal systems. Methylphenidate has thefollowing general formula:

The biological activity of methylphenidate, like many pharmaceuticals,fragrances, food additives and agrochemicals, is associated with itsabsolute molecular configuration. It is a “chiral compound,” i.e.,exists as different structural forms that have the ability to rotate theplane of plane-polarized light.

In describing such an optically active compound, the prefixes D and L orR and S are used to denote the absolute configuration of the moleculeabout its chiral center(s). The prefixes d and 1 or (+) and (−) areemployed to designate the sign of rotation of plane-polarized light bythe compound, with (−) or 1 meaning that the compound is levorotatory. Acompound prefixed with (+) or d is dextrorotatory. There is nocorrelation between nomenclature for the absolute stereochemistry andfor the rotation of an enantiomer. Thus, D-lactic acid is the same as(−) lactic acid, and L-lactic acid is (+). For a given chemicalstructure, these chiral compounds exist as a pair of enantiomers (calledstereoisomers) which are identical except that they arenon-superimposable mirror images of one another. A specific stereoisomermay also be referred to as an enantiomer, and a mixture of such isomersis often called an enantiomeric or racemic mixture.

Stereochemical purity can be of importance in the field ofpharmaceuticals, where 50 of the top 100 drugs worldwide exhibitchirality. See, for example, S.C. Stinson, Chemical & Engineering News,American Chemical Society, Washington, DC, Vol. 76 (Sep. 21, 1998) pg.83; and “Chiral Drugs,” S.C. Stinson, Chemical & Engineering News,American Chemical Society, Washington, DC, (Oct. 9, 1995). A case inpoint is provided by the L-form of the beta-adrenergic blocking agent,propranolol, which is known to be 100 times more potent than theD-enantiomer.

Furthermore, optical purity is important since certain isomers mayactually be deleterious rather than simply inert. For example, it issuggested that the D-enantiomer of thalidomide is a safe and effectivesedative when prescribed for the control of morning sickness duringpregnancy, while the corresponding L-enantiomer is believed to be apotent teratogen. There is a growing demand to market a chiral drug inenantiomerically pure form or substantially reduce the amount ofinactive enantiomers.

Methylphenidate exists as four enantiomers which are the(2R:2′R)-(+)-threo-enantiomer, the (2S:2′S)-(−)-threo-enantiomer, the(2R:2′S)-(+)-erythro-enantiomer, and the(2S:2′R)-(−)-erythro-enantiomer, but only the d-threo-methylphenidate issignificantly pharmacodynamically active. The degradants ofmethylphenidate are also essentially inactive.

The present invention is therefore directed to providing packagingmaterials for stabilizing a transdermal system during storage thatcontains a drug, particularly a chiral drug or active enantiomer(s)thereof, comprising a rubber modified acrylonitrile methyl acrylatecopolymer alone or in combination with a polyester.

SUMMARY OF THE INVENTION

It is therefore an object of this invention to provide a packagingmaterial for a transdermal drug delivery system that improves stabilityand shelf-life.

It is therefore another object of this invention to provide a packagingmaterial for a transdermal system that will not significantly react withor degrade the drug or other components of the system, and furtherprotect the system from degradation by environmental factors such aswater, air and/or light, during storage of the system prior to use.

It is also an object of this invention to provide a packaging materialfor a transdermal system that improves the stability of chiral drugs andactive enantiomers thereof contained in a transdermal system during itsstorage prior to use.

It is a further object of this invention to provide a packaging materialin the form of a laminate that increases the stability and shelf-life ofa transdermal system, and has increased tear resistance such that it canbe constructed into a substantially child resistant and/or proof pouch.

It is still another object of this invention to provide a packagingmaterial for a transdermal system in the form of a pouch comprisingbarrier materials to protect the system from degradation and loss byinternal and external factors, yet be sufficiently translucent so as topermit visual inspection and examination of the pouch contents.

It is additionally an object of this invention to provide a method formaking a pouch from laminate materials that provide improved stabilityand tear resistant properties, and. permit visual inspection of thepouch contents.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a cross-sectional illustration of the packaging material inthe embodiment of a laminate used to form a pouch.

DETAILED DESCRIPTION OF THE INVENTION

The foregoing and other objects are achieved by this invention whichprovides methods and materials for producing transdermal drug deliverysystem packaging wherein the drug incorporated in the transdermal systemremains substantially solubilized and stable in the carrier compositionof the transdermal system while the system is in storage prior to use.

The term “topical” or “topically” is used herein in its conventionalmeaning as referring to direct contact with an anatomical site orsurface area on a mammal including skin, teeth, nails and mucosa.

The term “mucosa” as used herein means any moist anatomical membrane orsurface on a mammal such as oral, buccal, vaginal, rectal, nasal orophthalmic surfaces.

The term “transdermal” as used herein means passage into and/or throughskin or mucosa for localized or systemic delivery of an active agent.

The term “system” as used herein is intended to broadly mean atransdermal drug delivery device topically applied to a mammal for thepurposes of providing some beneficial or therapeutic effect, andincludes all patch-type devices commonly referenced in the art asreservoir, matrix, adhesive matrix, in-line, membrane and multi-layerdevices, iontophorectic devices, and medicated bandages and pads.Further details and examples of transdermal systems generally aredescribed in U.S. Pat. Nos. 4,994,267, 5,006,108, 5,446,070, 5,474,787,5,656,286, 5,719,197, and Ser. Nos. 60/115,987 and 09/163,351, all ofwhich are assigned to Noven Pharmaceuticals, Inc. and incorporatedherein by reference.

The term “carrier composition” as used herein refers to any non-aqueousmaterial known in the art as suitable for transdermal drug deliveryadministration, and includes any polymeric material into which a drugmay be solubilized, alone or in combination or admixture with the otheradditives and excipients including solvents, permeation enhancers,diluents, stabilizers, fillers, clays, buffering agents, biocides,humectants, anti-irritants, antioxidants, preservatives, plasticizingagents, cross-linking agents, flavoring agents, colorants, pigments andthe like. Regardless of the type of transdermal system used to practicethe invention, the carrier composition is preferably substantially freeof water (i.e., the composition contains less than about 10% water byweight, preferably less than about 5% by weight, and most preferablyless than about 3% water by weight based upon the total weight of thecomposition prior to its topical application).

The term “solubilized” is intended to mean that in the carriercomposition there is an intimate dispersion or dissolution of the activeagent at the crystalline, molecular or ionic level. As such, the activeagent is considered herein to be in “non-crystallized” form when in thecompositions of the present invention.

As used herein, the term “flux” is defined as the absorption of the drugthrough the skin or mucosa, and is described by Fick's first law ofdiffusion:J=−D(dCm/dx),Where J is the flux in g/cm2/sec, D is the diffusion coefficient of thedrug through the skin or mucosa in cm2/sec and Dcm/dx is theconcentration gradient of the drug across the skin or mucosa.

The packaging material for use as the primary (or inner) layer 11 isthermoplastic polymers with good resistance to solvents and air, and inparticular, rubber modified acrylonitrile methyl acrylate copolymers.Such materials are disclosed, for example, in U.S. Pat. No. 3,426,102,and are commercially sold under the trademark Barex® by BP Chemicals,Inc., Cleveland, Ohio. Various material compositions of Barex® resinsare available, for example, Barex® 210, 2218 (which has a higher rubbermodified content than 210), and 214. An especially preferred material isBarex® 210.

In practice of the preferred embodiments of the invention, the thicknessof primary layer 11 is from about 0.5 mil to about 2.5 mil, morepreferably from about 0.75 mil to about 1.5 mil, and even morepreferably from about 1.0 mil to about 1.5 mil. While thinner andthicker widths may be employed, inner layer 11 should not be so thin soas to compromise its barrier and stabilizing properties, nor too thickso as to adversely affect sealing and packaging properties, such assealing to form a pouch.

As used herein, the term “pouch” refers to a package or other containerwhich contains a transdermal system and is sealed on at least one side.A pouch can comprise two sheets or laminates of the packaging materialof this invention that has been joined along all its edges. It may alsocomprise a single sheet or laminate that has been folded and sealed allalong its edges, or along all non-folded edges. It may further comprisea bag or pocket that is sealed along one or more edges. Sealing can beaccomplished by heat, ultrasound, laser, or adhesive and the like. Thepreferred packaging material is self-sealing (i.e., able to form astable bond between two facing surfaces of the same material without theuse of an adhesive).

While a pouch consisting of Barex® film alone can provide protectionfrom degradation and/or loss of methylphenidate base during storage ofsuch transdermal system, it is desirable to provide a secondary (orouter) layer 12 in order to augment its maintenance and stabilizingproperties, to increase tear resistance such that the pouch may functionas a child resistant/proof package, to provide a more cosmeticallyappealing covering, and/or to provide an easier printing substrate. Thesecondary layer 12 can be a film or laminate comprising any suitablematerial known in the art for packaging such as metal foils,polyethylenes, polyesters, vinyl acetate resins, ethylene/vinyl acetatecopolymers, polyurethanes, polyvinyl chloride, woven and non-wovenfabric, cloth and papers. In practice of the preferred embodiments ofthe invention, the thickness of secondary layer 12 is from about 0.2 milto about 3.0 mil, more preferably from about 0.2 mil to about 1.5 mil,and even more preferably from about 0,5 mil to about 1.0 mil. Whilethinner and thicker widths may be employed, secondary layer 12 shouldnot be so thin so as to compromise its barrier and tear resistanceproperties to the pouch, nor too thick so as to adversely affect sealingto primary layer 11 or packaging properties of the pouch.

Particularly preferred materials for use as the secondary layer are alsotranslucent materials such that the ability to view and inspect thecontents of the package is not lost. The preferred secondary layermaterial is a film of polyester. Polyester films further act to inhibittransmission of air and moisture.

Particularly preferred polyesters are those commercially sold under thetrademark Mylar® and Melinex by E.I. du Pont de Nemours and Company,Wilmington, Del., and include Mylar® S, Melinex® S and Melinex® 800polyester films.

Secondary layer 12 can be affixed to primary layer 11 by any techniqueknown in the art. Attachment by means of heat fusion or an adhesive,particularly a pressure-sensitive adhesive, is preferred. Use of anadhesive is preferred in order to achieve greater tear resistanceproperties which are desirable in creating child resistant/proofpackaging.

An adhesive is a pressure-sensitive adhesive within the meaning of theterm as used herein if it has the properties of a pressure-sensitiveadhesive per se or if it functions as a pressure-sensitive adhesive byadmixture with tackifiers, plasticizers, cross-linking agents or otheradditives.

Pressure-sensitive adhesives include all of the non-toxic natural andsynthetic polymers known or suitable for use in transdermal systemsincluding solvent-based, hot melt and grafted adhesives, and may be usedalone or in combinations, mixtures or blends. Examples of suitableadhesives include polyacrylates, polysiloxanes, silicones, rubbers,gums, polyisobutylenes, polyvinylethers, polyurethanes, styrene blockcopolymers, styrene/butadiene polymers, polyether block amidecopolymers, ethylene/vinyl acetate copolymers, and vinyl acetate basedadhesives. Suitable polysiloxanes include those commercially availableand sold under the trademark BIO-PSA® by Dow Corning Corporation,Midland, Mich.

The pressure-sensitive adhesives particularly useful in practicing thisinvention include polyacrylates of one or more monomers of acrylic acidsor other copolymerizable monomers. Polyacrylate adhesives also includepolymers of alkyl acrylates and/or methacrylates and/or copolymerizablesecondary monomers, or monomers with functional groups. The term“polyacrylate” is intended to be used interchangeably with the termsacrylic, acrylate and polyacrylic as used herein and as known in theart.

Suitable pressure-sensitive acrylic adhesives are commercially availableand include those sold under the trademark DURO-TAK® by National Starchand Chemical Company, Bridgewater, N.J., and GELVA® MultipolymerSolution by Solutia, Inc., St. Louis, Mo.

In practice of the preferred embodiments of the invention, the adhesiveis applied to secondary layer 12 and dried to a thickness that shouldpreferably not exceed about 1 mil, and is preferably in a range fromabout 0.3 mil to about 0.75 mil, prior to pressure sealing the adhesivecoated secondary layer 12 to primary layer 11.

In order to provide protection from light for drugs which may further besubject to degradation by light, it may be desirable to use a modifiedform of secondary layer 12 material. For example, the material may betinted to provide a partial barrier affecting only certain wavelengthsof light, or be substantially opaque as in a metalized polyester film.

In a preferred embodiment, the packaging material is a laminatecomprising (a) primary layer 11 that will not significantly absorb thedrug or other components of the transdermal carrier composition, orotherwise negatively affect the physical characteristics of the drug orother components of the transdermal carrier composition, and (b)secondary layer 12 that augments the maintenance and protectioncharacteristics of the inner layer, but further imparts increased tearresistance such that the packaging material is substantially childresistant/proof. The novel laminate packaging material can be in anyconvenient form that permits the effective closure of a transdermalsystem, such as a pouch. The perimeter of the pouch can be in anydesign, shape or form, irregular or uniform. Uniform shapes such assquares, rectangles, circles and ovals are preferred in order tofacilitate the sealing and manufacturing processes.

Reference to FIG. 1 shows a cross-sectional view of a preferredembodiment of the packaging laminate in the form of pouch 9 containingtransdermal system 10 according to the present invention. The primarylayer 11 comprising a rubber modified acrylonitrile methyl acrylatecopolymer is affixed to secondary layer 12 comprising a polyester bymeans of adhesive 13. The laminate in the form of pouch 9 may be sealedat the edges for example by heat. The novel laminate packaging materialin the form of a pouch not only provides maintenance and protection ofthe drug contained in the transdermal system from degradation frominternal and environmental factors, but further provides tear resistancecharacteristics suitable to make it child resistant/proof.

The present invention is generally directed to packaging materials forstabilizing a transdermal system that contains methylphenidate as thedrug. The methylphenidate used for testing in the examples was in baseform and comprised a racemate of about 50% each ofd-threo-methylphenidate and 1-threo-methylphenidate. The majordegradants include ritalinic acid and the erythro-enantiomers (both d:1and 1:d). The term “degradant” as used herein refers to any impurity,metabolite, non-metabolite, enantiomer and the like that exhibits no orsignificantly lower pharmacodynamic activity for a particulartherapeutic purpose or deserved beneficial effect than the drug moleculeor another enantiomer thereof. Correspondingly, an “active” enantiomerrefers to the isomer of a chiral drug that exhibits greaterpharmacodynamic activity that its counterpart enantiomers. Loss ofactive drug, either by absorption into the packaging materials or bydegradation during storage, reduces the amount of the active enantiomer,thus reducing the amount of active drug available to deliver atherapeutically effective amount.

As used herein, “therapeutically effective” means an amount of drug thatis sufficient to achieve the desired local or systemic effect or result,such as to prevent, cure, diagnose, mitigate or treat a disease orcondition, when applied topically over the duration of intended use. Theamounts necessary are known in the literature or may be determined bymethods known in the art, but typically range from about 0.1 mg to about20,000 mg, and preferably from about 0.1 mg to about 1,000 mg, and mostpreferably from about 0.1 to about 500 mg per human adult or mammal ofabout 75 kg body weight per 24 hours.

Although the particularly preferred embodiments of the present inventionare generally directed to packaging materials useful for a transdermalsystem containing methylphenidate, particularly in base form, packagingmaterials of the present invention are useful for systems containing anydrug that is incompatible (unstable) with commonly used packagingmaterials as those described in the examples herein (such aspolyethylene or polypropylene) other than nicotine. Such drugs includechiral drugs, for example, ceftriaxone, thalidomide, propranolol,ibuprofen, ketoprofen, naproxen, peroxetine, finasteride, sertraline,paclitaxel, terfenadine, verapamil, enalapril, lisinopril, ifosamide,methyldopa, indacrinone, bupivacaine, loxiglumide, amlodipine,pyridinium, levoslmedan, ondansetron, salmeterol, ketorolac, doxazosin,cisapride, albuterol, oxybutynin, selective serotonin reuptakeinhibitors such as fluoxetine, loratadine, fexofenadine, cetirizine,formoterol, triptans such as sumatriptan, doxazosin, zolpidem,sibutramine, atorvastatin, nadolol, abacavir, citalopram, nifedipine,glitazones such as troglitazone, progliotazone, and rosiglitazone,clorazepate, lorazepam, oxazepam, temazepam, omeprazole, levofloxacin,captopril, and diltiazem.

The term “drug” as used herein is intended to have the broadest meaningpossible, and be used interchangeably with active agent, pharmaceutical,medicament and any substance intended to provide a beneficial effectincluding a therapeutic, prophylactic, pharmacological, or physiologicalsubstance, cosmetic and personal care preparations, and mixturesthereof. More specifically, any substance that is capable of producing apharmacological response, localized or systemic, irrespective of whethertherapeutic, diagnostic, cosmetic or prophylactic in nature, is withinthe contemplation of the invention. It should be noted that the activeagents can be used singularly or in combinations and mixtures. There isno limitation on the type of active agent that can be used in thisinvention. However, active agents that are solid at room temperature arepreferred.

The active agents contained in the carrier composition can be indifferent forms depending on the solubility and release characteristicsdesired, for example as neutral molecules, components of molecularcomplexes, and pharmaceutically acceptable salts, free acids or bases,or quaternary salts of the same. Simple derivatives of the drugs such aspharmaceutically acceptable ethers, esters, amides and the like whichhave desirable retention and release characteristics but which areeasily metabolized at body pH, and enzymes, pro-active forms, pro-drugsand the like, can also be employed.

EXAMPLES

The following procedure is illustrative of how to generally prepare atransdermal drug delivery system, and particularly describes thetransdermal system used in testing the stability of a transdermal systemstored in pouches of various packaging materials described in theexamples.

A transdermal system containing methylphenidate base in apressure-sensitive adhesive carrier composition was prepared bycombining 6.0 part methylphenidate base along with 4.5 parts of ethylcellulose (Ethocel® 20, Dow Chemical Corp., Midland, Mich.) in 22.75parts of ethyl acetate. Next, 8.6 parts of a polyacrylate adhesive (GMS3067; Solutia Inc., St. Louis, Mo.) and 24.5 parts of a polysiloxaneadhesive (BIO-PSA® 7-4302; Dow Corning Corp., Midland, Mich.) were addedand thoroughly mixed. The carrier composition was then wet caste at 20mils, with a wet gap bar, onto a fluorocarbon release liner (Scotch Pak®1022, 3M, Minneapolis, Minn.) and run through an oven to evaporatevolatile solvents. The dry composition was laminated to a (polyester)backing film (Scotch Pak® 1012, 3M, Minneapolis, Minn.). The carriercomposition had the ingredient concentrations on a dry weight basis asshown below. Ingredient Dry Weight % Polysiloxane Adhesive  50(BIO-PSA ® 7-4302) Polyacrylate Adhesive  15 (GMS 3067) Ethyl Cellulose 15 (Ethocel ® 20) Methylphenidate Base  20 100

Transdermal system samples of 10 cm² were then die cut and placed into2.5 in² heat-sealed pouches comprised of the various materialcombinations described in each of the following examples.

Example 1

A 1.25 mil film of Barex® 210 heat laminated to 0.35 mil aluminum foil.The aluminum foil was then bonded to 35# Kraft paper using an adhesive(laminate material manufactured by Richmond Technology, Redlands,Calif.).

Example 2

A 1.25 mil film of Barex® 210 laminated with a polyester film using aurethane adhesive commercially available as 94035 and sold by LawsonMardon (Shelbyville, Ky.).

Example 3

A 1.25 mil film of Barex® 210 laminated with aluminum foil using anadhesive, which is then laminated to a polyester film using an adhesive,which is commercially available as 90580 and sold by Lawson Mardon.

Example 4

A 1.25 mil film of Barex® 210 (provided by Greenway Plastics IndustriesCorporation, Wayne, N.J.).

Example 5

Same as Example 1.

Example 6

A 2.0 mil film of Scotch Pak® 1012 (a polyester film laminated to aethylene/vinyl acetate heat seal layer manufactured by 3M).

Example 7

A 2.0 mil film of Scotch Pak® 1009 (a polyester film laminated withaluminum foil and ethylene/vinyl heat seal layer manufactured by 3M).

Example 8

A 3 mil film of a proprietary laminate barrier film commerciallyavailable as 5488-9913 and sold by Kappler Protective Apparel & Fabrics,Inc. (Guntersville, Ala.).

Example 9

A 1.25 mil film of Barex® 210 laminated to a 2 mil polyester film usingan acrylate adhesive (Duro-Tak® 87-2296 by National Starch and ChemicalCorporation, Bridgewater, N.J.).

Example 10

Same as Example 9 except a 0.92 mil polyester film was used.

Example 11

Same as Example 9 except that a 0.2 mil polyester film was used.

Example 12

A 3 mil film of a proprietary laminate barrier film commerciallyavailable as 5488-99A and sold by Kappler Protective Apparel & Fabrics,Inc.

Example 13

A 2 mil polyester film.

Example 14

A 1.25 mil film of Barex® 210 heat sealed into pouch within aheat-sealed pouch of 2 mil polyester.

Three samples of each example containing the transdermal system werethen placed in an oven at 80° C. for 4 days to accelerate aging (i.e.,simulate shelf-life storage of about 2 years). The transdermal systemswere then removed from the pouches, and placed in an extraction solutionof acidified methanol after removal of the release liner. The extractionsolution containing the system was sonicated for 45 minutes at roomtemperature. Aliquot samples were then extracted and examined byhigh-pressure liquid chromatography to determine and measure the percentof degradants and active drug loss.

The same extraction procedure was employed to the pouch materials todetermine and measure the amount of active drug (i.e.,d-threo-methylphenidate) absorbed such materials in mg by dry weight.The results are set forth in Table I. TABLE I Total Drug DrugDegradation Loss Absorption Example % (%) (mg)  1* 0.1 0 0.108 2 9.710.1 0.440 3 25.3 23.7 0.254 4 8.6 6.2 0.265 5 15.0 14.1 0.209 6 8.316.9 2.979 7 8.6 19.2 3.182 8 8.5 12.1 1.692 9 8.7 7.9 0.176 10  8.7 6.60.107 11  8.6 6.9 0.117 12  8.7 21.4 2.217 13  8.6 4.8 0.204 14  8.7 6.20.147*Example 1 was used as a control which was maintained at roomtemperature for 4 days.

The data shows significant degradation occurs when a metal foil isincorporated into packaging laminate without first providing a barrier,such as by use of a polyester film; between the metal foil and the drug.While examples 4 and 15 consisting of single layer films provide goodstability, they are not self-sealing and are different to heat seal andobtain an effective closure. Significant drug loss is also observed inthe presence of vinyl acetate. The examples using the Barex® andpolyester film laminates demonstrated good stability over time.

1. A method of inhibiting the loss of the active enantiomers of a chiraldrug in a carrier composition of a transdermal system, comprising thesteps of: providing a laminate package material comprising: (i) an innerlayer comprising a thermoplastic polymer film, wherein said layer isfree of polyolefins, metal foil and vinyl acetate; and (ii) an outerlayer affixed to said inner layer; providing a non-aqueous carriercomposition of a transdermal system comprising a chiral drug or activeenantiomers thereof that degrades or is unstable when exposed to vinylacetate and metal foil materials; placing said carrier compositionwithin a pouch of the laminate packaging material; and sealing saidpouch along one or more edges of the inner layer, wherein the chiraldrug or active enantiomers thereof excludes nicotine.
 2. A methodaccording to claim 1, wherein the inner layer of the laminate packagingmaterial is self-sealing.
 3. A method according to claim 1, wherein theinner layer is a film of rubber modified acrylonitrile methyl acrylatecopolymers.
 4. A method according to claim 3, wherein the outer layercomprises at least one polyester film affixed to the inner layer.
 5. Amethod according to claim 4, wherein the outer layer is affixed to theinner layer by means of an adhesive.
 6. A method according to claim 1,wherein the laminate packaging material is child resistant.
 7. A methodaccording to claim 1, wherein the laminate packaging material istranslucent.
 8. A method according to claim 1, wherein the chiral drugis selected from the group consisting of methylphenidate, apharmaceutically acceptable salt or base of methylphenidate, and activeenantiomers thereof.